As Schizophrenia is known to be associated with hereditary and extra-hereditary risk factors to search for extra-hereditary factors we examined the plasma proteins, that are known to vary in response to external factors. To minimize the genetic factors we compared plasma proteins from pairs of monozygotic twins who were discordant for schizophrenia. Plasma proteins are generally synthesized in the liver and certain classes of them, such as the acute phase proteins, demonstrate robust quantitative changes with inflamation and other forms of metabolic stress. In this endeavor we employed a number of methods that we developed ranging from: high resolution two dimensional protein electrophoresis, sensitive protein silver stains, and computerized densitometry. These studies were designed to determine whether there are quantitative differences that might provide some insight into the nature of extra-hereditary factors associated with this disease. These studies revealed a greater variation in the plasma protein composition between pairs of twins discordant for schizophrenia than between pairs of normal monozygotic twins and monozygotic twins concordant for schizophrenia. Some of the protein differences observed were in the acute phase proteins, such as haptoglobin, suggesting a systemic alteration in metabolism in schizophrenia, as might be caused by a systemic inflammatory abnormality. These findings are in agreement with our previous observations in which we found an increased concentration of fibrin (from fibrinogen) and haptoglobin in the spinal fluid of patients with: schizophrenia, Alzheimer's disease, and manic depressive disease. While these proteins appear to have disparate functions (fibrin is involved in clotting and haptoglobin is involved in heme metabolism) they both are also acute phase proteins which are often increased in concentration in inflammatory conditions. In addition, several unidentified polypeptide spots were elevated only in the schizophrenic twin. One of these proteins (spot 782) was also found to be significantly elevated (p < 0.001) in the plasma of unrelated schizophrenic individuals (n=75). In our study, samples from normal control monozygotic twins did not significantly differ from one another to a greater extent than the variations found in duplicate electrophoretograms from the same individual. It would be interesting to know if the differences between the discordant twins were present prior to the onset of the disease since they have, presumably, as similar an environment prior to onset as do normal control twins. The plasma protein differences observed between the discordant monozygotic twins could be due to: effects of the pharmaceutical agents used in the treatment of the schizophrenic twin, the stress caused by the disease state, or underlying general pathophysiology affecting organs beyond the CNS. These results may indicate that extra-hereditary factors act systemically or at least are not limited to the CNS in schizophrenia, and that chronic systemic inflammation may play a role in or provide clues to the pathophysiology of schizophrenia. To facilitate our analysis of protein alterations in disease states, the Laboratory has developed a relational database, in collaboration with Dr. Lemkin at the NCI, to provide a linkage between known disease-associated protein alterations and quantitative variations of plasma proteins separated by high-resolution electrophoresis. As high-resolution two-dimensional protein electrophoresis allows the simultaneous evaluation of 1,500 to 3,000 proteins in complex solutions, such as the body fluids a relational database is essential for the analysis of qualitative and/or quantitative changes of these proteins in disease states. The laboratory has linked this database to other protein and genomic databases on the Internet.